Penicillin compositions and their administration

ABSTRACT

Orally administrable compositions active against Gram-positive and Gram-negative bacteria comprising certain mono-esters of Alpha -carboxypenicillins wherein the Alpha -carboxy group is esterified and a pharmaceutically acceptable non-toxic carrier formed into dosage units and filled into capsules or compressed into tablets and a method of treating infections due to such bacteria by means of such compositions.

United States Patent [19] Hardy et al.

[ Apr. 29, 1975 l i PENICILLIN COMPOSITIONS AND THEIR ADMINISTRATION [75] Inventors: Kenneth David Hardy. Horsham;

John Herbert Charles Nayler.

Dorking; Edward Raymond Stove, Redhill, all of England [73} Assignee: Beecham Group Limited. Middlcsex,

England 221 Filed: July 18, I974 21 Appl.No.:489,6l2

Related U.S. Application Data [63] Continuation-impart of Ser, No, H1740. Feb. 8, 197 l Patv No. 3.853.849 which is a continuation of Scr. No 833.848. May 29, I969 abandoned. which is a continuation of Ser No, 679.995. No: 2 l967 abandoned.

[IiUI Foreign Application Priority Data Nov. 5. I966 United Kingdom .4 49697166 Jan. 27. i967 United Kingdom 4079/6? 1 U.S. Cl. 424/27l Int. Cl. H6lk 27/00 Field of Search 424/271; 260/239.l

[56] References Cited UNITED STATES PATENTS ll/l966 Brain et al. .4 260/2391 1/1970 Brain et all .i 260/2391 PI'IH'I(H' Examiner-Jerome D. Goldberg [57] ABSTRACT 12 Claims. No Drawings PENICILLIN COMPOSITIONS AND THEIR ADMINISTRATION This application is a continuation-in-part of application Ser. No. 113,740, filed Feb. 8, l971, now US. Pat. No. 3,853,849, which is a continuation of Ser. No. 833,848, filed May 29, 1969 which in turn is a continuation of Scr. No. 679,995, filed Nov. 2, I967 and both now abandoned.

This invention relates to new penicillins, and more particularly to a class of cx(aryloxycarbonyland a(alkoxycarbonyl)-aralkylpenicillins.

These penicillins are active against Gram-positive and Gram-negative bacteria which makes them useful as therapeutic and prophylactic agents against bacterial infections in animals, including man and poultry.

The new penicillins are of the general formula (I) n.ca.co NH ea ca I ca l eoon I l 3 CO ll CH-COOH wherein R is a phenyl, substituted phenyl, fury] or thienyl group and R is a phenyl, substituted phenyl, naphthyl or substituted naphthyl group or the group ium, ammonium and substituted ammonium salts, e.g., salts of such non-toxic amines as trialkylamines( including triethylamine), procaine, dibenzylamine, N-benzylbeta-phenethylamine, l-ephenamine, N,N- dibenzylethylenediamine, dehydroabietylamine, N,N'- bis-dehydroabietylcthylenediamine, and other amines which have been used to form salts with benzylpenicillin.

The penicillins of formula (l) are prepared by acylating o-aminopenieillanic acid with a reactive acylating derivative of formula (II) R ease. Q

cooa

in which R and R are as defined above and Q is a functional group of the type used for acylating primary amines such as a chlorine or bromine atom (i.e., II is an acyl halide), an azido group, an acyloxy or alkoxycarbonyloxy group (i.e. II is an acid anhydride or mixed anhydride) or a l-imidazolyl or N,N'-disubstituted isoureido group (i.e., II is an intermediate formed from the half ester of an cit-substituted malonic acid and a condensing agent such as carbonyldiimidazole or a N,N'-disubstituted carbodiimide such as dicyclohexylcarbodiimide). Some of these acylating agents of formula (II) are unstable substances which are preferably freshly prepared in a suitable solvent below room temperature and used in situ.

The penicillins of formula (I) contain at least one asymmetric carbon atom and so a single compound as represented by formula (I) may exist in several different spatial configurations. However, since all of the compounds of one formula are merely epimers or stereoisomers of each other it is to be understood that they are all covered by the definition of formula (I); thus the invention covers the D and L forms as well as the DL mixtures.

This invention particularly relates to orally administrable compositions which contain certain new a-carboxypenicillin, mono-esters and more particularly contain the phenyl and lower alkyl phenyl esters of carbenicillin and ticarcillin wherein in formula (l) above R is phenyl or 3-thienyl and R is phenyl or lower alkyl phenyl, e.g., methylphenyl. These penicillin esters are active against Gram-positive and Gram-negative bacteria when orally administered which makes then useful as therapeutic and prophylactic agents against bacterial infections in animals, including man and poultry.

The new penicillins for use in the compositions of the present invention are thus of the formula (IA):

wherein R is a phenyl or 3-thienyl group and R is phe nyl or lower alkyl phenyl. These compounds are claimed as such in said application Ser. No. 113,740 and are mono-esters of a-carboxypenicillins wherein the a-carboxy group is esterified as indicated. The unesterified a-carboxypenicillins are described in U.S. Pat. Nos. 3,142,673 and 3,282,926 and two such compounds, namely carbenicillin (aforesaid general for mula (IA) wherein R phenyl, R hydrogen) and ticarcillin (aforesaid general formula (lA) wherein R 3-thienyl, R hydrogen) are particularly active anti bacterial agents against both Gram-positive and Gramnegative bacteria. However they must be administered parenterally since they are not absorbed after oral administration. On the other hand, the present monoesters are especially suitable for oral administration.

Accordingly the present invention provides a composition for the treatment of infections due to Grampositive and Gram-negative bacteria comprising an antibiotically effective amount of a mono ester of an a-carboxypenicillin of the aforesaid formula (IA) or a non-toxic pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable nontoxic carrier formulated for oral administration in unit dosage form.

A penicillin of formula (IA) may be presented for biological use in the form of its free acid or as a non-toxic salt and this may be presented alone or in association with a suitable pharmaceutical carrier for oral administration. This term is to be interpreted in the widest sense to include such carriers as foodstuffs as well as diluents, binders, solvents, flavouring agents, colouring agents, and other conventional vehicles and additives in the form of unit dose units such as tablets or capsules or other containers or elixirs or suspensions for oral administration.

Thus, as suggested in U.S. Pat. No. 3,142,673 for the free a-carboxypenicillins, the penicillins of formula (IA) may be administered alone or in combination with a pharmaceutical carrier on the basis of standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch, milk sugar, certain types of clay, etc., or in capsules alone or in admixture with the same or other conventional excipients. They may also be administered orally in the form of potable elixirs or suspensions which may contain flavouring or colouring agents. With orally administrable compositions containing penicillins the unit dosage form will normally comprise at least 125 mg of the penicillin in order to provide an antibacterially effective dose but not more than 1,000 mg because of the difficulty of swallowing more than this amount having regard to the unpalatability of penicillin compounds. Thus the present compositions contain l25-1,000 mg per unit dose of the penicillin mono-ester and preferably from 250-500 mg of the penicillin mono-ester of formula (IA). By way of example, the phenyl ester of ticarcillin (250 mg) or the phenyl ester of carbenicillin (500 mg) is filled into unit dose gelatin capsules which are then sealed. Similarly, the tolyl ester of ticarcillin (250 mg) is filled into unit dose capsules.

The invention is illustrated by the following examples.

EXAMPLE I Mono-phenyl phenylmalonate Phenylmalonic acid (27 g. 0.15 mol.) was mixed with dry ether (80 ml.) and treated with thionyl chloride (l7.85 g. l0.9 ml. l equiv.) and dimethylformamide (4 drops). The mixture was refluxed for 3 hours on a hot water bath. The solvent was evaporated under reduced pressure and the residue dissolved in fresh dry ether (80 ml.) Phenol (l4.l g. 0.15 mol.) was added all at once and the mixture refluxed for a further 2 hours. The reaction was cooled to room temperature, washed with water (25 ml.) and extracted with saturated sodium bicarbonate solution until the extracts were alkaline. The combined aqueous extracts were washed with ether (I ml.) and acidified with 5N. hydrochloric acid. The precipitated oil was extracted exhaustively with methylene chloride. The combined organic extracts were washed thoroughly with water (6 X I20 ml.) dried over anhydrous magnesium sulphate and evaporated. The solid residue was crystallised from benzene to give a colourless crystalline solid 30.2 g. (78.7%) m.p. ll5l 17C. (Found: C,73.79; H,5.]4. C H, O .l/2 C H requires: C,73.25; H.512).

01-(Phenoxycarbonyl)benzylpenicillin-sodium salt Mono-phenyl phenylmalonate (5.12 g. 0.02 mol.) was mixed with thionyl chloride (20 ml.) and heated in a water bath at 75C for 1 hour. The excess thionyl chloride was evaporated under reduced pressure. The residue was mixed with dry benzene ml.) and again evaporated to dryness to remove residual thionyl chloride. The final residue was dissolved in dry acetone I00 ml.) and added, with stirring, to a solution of 6- aminopenicillanic acid (4.32 g. 0.02 mol) in water I00 ml.), N. sodium hydroxide ml.), N. sodium bicar' bonate solution ml.) and acetone ml.) cooled to 12C. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was extracted with ether (3 X ml.) and the extracts discarded. The aqueous layer was covered with ether (60 ml.) and acidified with N. hydrochloric acid to pH 2. The ether layer was separated and the aqueous layer extracted with further ether (2 X 60 ml.). The combined ether extracts were washed with water (20 ml.) and extracted with N. sodium bicarbonate solution to pH 7. The neutral aqueous extract was evaporated under reduced temperature and pressure. The residue was dried over phosphorous pentoxide in vacuo to give 6.7 g. (70.4%) of the penicillin salt as an amorphous solid. The solid, when dissolved in ethanol (50 ml.) at room temperature gave on standing 30 minutes the penicillin salt as a colourless crystalline solid 5.23 g. (78.l% of recovery).

EXAMPLE 2 Mono-( o-ethoxycarbonylphenyl )phenylmalonate Phenylmalonic acid (27 g. 0.15 mol.) in dry ether ml.) was converted to the mono-acid chloride and reacted with ethyl salicylate (24.9 g. 21.92 ml. 0.15 mol) as described in Example I. The crude product was recrystallised frorn benzene/60 80 petroleum ether to give a colourless crystalline solid 13.2 g. (26.8%)m.p. 98l00C. (Found: C, 66.06; H,4.85 C,,,H, O re quires Q6586; H, 4.91).

a-(o-Ethoxycarbonylphenoxycarbonyl )benzylpenicil- [in sodium salt Mono-(o-ethoxycarbonylphenyl)phenylmalonate (3.28 g. 0.01 mol.) was converted to the acid chloride and reacted with o-aminopenicillanic acid (2.16 g. 0.0] mol.) as described in Example l, to give the penicillin sodium salt 4 g. (73%) as a colourless non-crystalline solid.

EXAM PLE 3 Mono-( o benzyloxycarbonylphenyl )phenylmalonate Phenylmalonic acid (27 g. 0.15 mol.) in dry ether (80 ml.) was converted to the monoacid chloride and reacted with benzyl salicylate (34.2 g. 29.1 ml. 0.15 mol.) as described in Example I. The crude product was recrystallised from benzene/6080 petroleum ether to give a colourless crystalline solid 13.75 g. (23.5%) m.p. l05l08C. (Found: C, 70.03; H, 4.51. C H O requires C, 70.75; H,4.65).

a-(o-Benzyloxycarbonylphenoxycarbonyl )benzylpenicillin sodium salt Mono-( o-benzyloxycarbonylphenyl)phenylmalonate (3.9 g. 0.01 mol.) was converted to the acid chloride and reacted with 6-aminopenicillanic acid (2.16 g. 0.01 mol.) as described in Example 1 to give the penicillin sodium salt 4 g. (65.5%) as a colourless non-crystalline solid.

EXAMPLE 4 Mono-( 2,6-dimethoxypheny1)phenylmalonate Phenylmalonic acid (27 g. 0.15 mol.) in dry ether (80 ml.) was converted to the mono-acid chloride and reacted with 2,6-dimethoxy-phenol (23.1 g. 0.15 mol.) as described in Example l The crude product was recrystallised from benzene/6080 petroleum ether to give 30.2 g. (63.7%) of colourless crystals m.p. l3 l-l33C. (Found: C,64.57; H.501. C H O requires C,64.54; H,5.10.

a-( 2 ,6-Dimethoxyphenoxycarbonyl )benzylpenicillin sodium salt Mono-2,6-dimethoxypheny1 phenylmalonate (3.16 g. 0.01 mol.) was converted to the acid chloride and re acted with 6-aminopenici1lanic acid (2.16 g. 0.01 mol) as described in Example 1 to give the penicillin sodium salt 4.1 g. (76.5%) as a colourless non-crystalline solid.

EXAMPLE 5 Mono-2-naphthyl phenylmalonate a-( Z-Naphthoxycarbonyl )benzylpenicillin sodium salt Mono-2-naphthyl phenylmalonate (3.06 g. 0.01 ml.) was converted to the acid chloride and reacted with 6- aminopenicillanic acid (2.16 g. 0.01 ml.) as described in Example 1 to give the penicillin sodium salt 2.9 g. (55.1%) as a cream coloured non-crystalline solid.

EXAM PLE 6 Mono-phenyl 3-thienylmalonate 3-Thienylmalonic acid (9.3 g. 0.05 mol.) in dry ether (30 ml.) was converted to the mono-acid chloride and reacted with phenol (4.7 g. 0.05 mol.) as described in Example 1. The crude solid was recrystallised from benzene/60-80 petroleum ether to give a colourless crystalline solid 2.89 g. (22.1%) m.p. 120122C. (Found: C,59.33; H,3,68; 5.11.78. C, H, O ,S requires: C, 59.51; H,3.84; S,12.33.).

a-Phenoxycarbonyl)3-thienylmethylpenicillin sodium salt Mono-phenyl B-thienylmalonate (2.62 g. 0.01 mol) was converted to the acid chloride and reacted with 6- aminopenicillanic acid (2.16 g. 0.01 ml.) as described in Example 1 to give the penicillin sodium salt 3.4 g. (70.6%) as a cream coloured non-crystalline solid.

EXAMPLE 7 a. Mono-2,2,2-trichloroethyl phenylmalonate Phenylmalonic acid (54 g. 0.3 mol) was mixed with dry ether (160 ml.) and treated with thionyl chloride (35.7 g. 21.8 ml. 1 equivalent) and dimethylformamide (8 drops). The mixture was refluxed for 4 hours on a hot water bath. The solvent was evaporated under reduced pressure, and the residue was dissolved in fresh dry ether (160 ml.). 2,2,2-Trichloroethano1 (44.85 g. 0.3 mol.) was added all at once and the mixture heated under reflux for a further 2 hours. The reaction was cooled to room temperature, washed with water (50 m1.) and extracted with saturated sodium bicarbonate solution until the extracts were alkaline. The combined aqueous extracts were washed with ether (200 ml.) and acidified with 5 N. hydrochloric acid. The precipitated oil was extracted exhaustively with methylene chloride. The combined organic extracts were washed thoroughly with water (6 X 240 ml.), dried over anhydrous magnesium sulphate and evaporated. The oily residue was triturated with light petroleum (boiling range 6080C) to give a colourless crystalline solid 58.8 g. (62.9%) m.p. 54-56C. The product was recrystallised from cyclohexane to give pure material 40 g. (42.8%) m.p. 5860C. (Found: C,43.09; H,3.11; Cl, 33.91. C H O Cl requires: 42.40; H,2.9l', C1 34.15%).

b. a-(2,2,2-Trichloroethoxycarbonyl)benzylpenicillin sodium salt Mono-2,2,2-trich1oroethyl phenylmalonate (9.35 g. 0.03 mol.) was mixed with thionyl chloride (30 m1.) and heated in a water bath at C for 1 hour. The excess thionyl chloride was evaporated under reduced pressure. The residue was mixed with dry benzene (5 ml.) and again evaporated to dryness to remove resid ual thionyl chloride. The final residue was dissolved in dry acetone 150 m1.) and added, with stirring, to a solution of 6-aminopenicillanic acid (6.4 g. 0.03 mol.) in water (150 ml.), N.sodium hydroxide (30 ml.), N.sodium bicarbonate solution (45 m1.) and acetone (75 ml.) cooled to 12C. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was extracted with ether (3 X 100 ml.) and the extracts were discarded. The aqueous layer was covered with ether 100 m1.) and acidified, with rapid stirring, to pH 2 with N.hydrochloric acid. The ether layer was separated and the aqueous layer extracted with ether (2 X 100 ml.). The combined ether extracts were washed with water (30 ml.) and extracted with N.sodium bicarbonate solution to pH 7. The neutral aqueous extract was evaporated under reduced temperature and pressure. The residue was dried over phosphorus pentoxide in vacuo to give 1 1.2g. (70.2%) of the penicillin salt as an amorphous solid.

EXAMPLE 8 Mono-2-phenoxyethyl phenylm alon ate Phenylmalonic acid (27 g. 0.15 mol.) in dry ether ml.) was converted to the mono acid chloride and reacted with 2-phenoxyethanol (20.7 g. 188ml. 0.15 mol) by the method described in Example 7(a) to give 328g. (72.9%) of crude ester m.p. 7779C. This was recrystallised from a mixture of light petroleum (boiling range 6080C) and benzene to give 29.4 g. (65.3%) of a colourless crystalline solid m.p.

79.5*81.5C. (Found: C.o8.23; H.585. C H O requires (2.68.0; H5379? a( 2 Phenoxyethoxycarbonyl )benzylpenicillin sodium salt Mono-2-phenoxyethyl phenylmalonate (9 g. 0.03 mol.) was converted to the acid chloride and reacted with o-aminopenicillanic acid (6.48 g. 0.03 mol.) by the method described in Example 7(b) to give the penicillin 14.5 g. (93%) as a colourless non-crystalline solid.

EXAMPLE 9 Mono-2-( p-toluenesulphonyl )ethyl phenylmalonate Phenylmalonic acid (18 g. 0.1 mol.) in dry ether (60 ml.) was converted to the mono acid chloride and reacted with 2-(ptoluenesulphonyl)ethanol (20 g. 0.1 mol) by the method described in Example 7(a). The crude product was recrystallised from benzene to give 89 g. (24.6%) of colourless crystals m.p. 79-81C. Found: C.60.49; H.519; 5.8.75. C H O S requires: C5967; H.500; 5.884%).

a-[ 2-( p-Toluenesulphonyl )ethoxycarbonyl lbenzylpenicillin sodium salt Mono-24p-toluenesulphonyl)ethyl phenylmalonate (3.62 g. 0.01 mol.) was converted to the acid chloride and reacted with b-aminopenicillanic acid (2.16 g. 0.01 mol.) by the method of Example 7(b) to give the penicillin 4.6 g. (79%) as a colourless non-crystalline solid.

EXAMPLE l Mono-2-nitrobuty1 phenylmalonate Phenylmalonic acid (27 g. 0.15 mol.) in dry ether (80 ml.) was converted to the mono acid chloride and reacted with 2-nitrobutano1-l (17.9 g. 15.7 ml. 0.15 mol.) by the method of Example 7(a). The crude product after three recrystallisations from benzene/6- 0-80C light petroleum gave colourless platelets 5.5 g. (13.1%) m.p. 80-8-2C. designated the oz-stereoi someric form. (Found: (1,5583; H.598; N, 4.91. C H O N requires C,55.50; H.538; N,4.99%).

Dilution of the mother liquors from the first recrys tallisation above gave a crude solid which, after four recrystallisations and from benzene/6080C light petroleum gave a granular crystalline solid 0.8 g. m.p. 79-81C. designated the B-stereoisomeric form. (Found: C.55.62; H.550; N501. C, H O N requires (3.55.50 H, 5.38; N,4.99%). Mixed m.p. of the two forms gave m.p. 6674C.

a-(Z-Nitrobutoxycarbonyl)benzylpenicillin sodium salt i. The oz-form of 2-nitrobutyl phenylmalonate (2.81 g. 0.01 mol.) was converted to the acid chloride and reacted with o-aminopenicillanic acid by the method of Example 7(b) to give the pencillin 3.9g. (77.9%) as a cream coloured non-crystalline solid.

ii. The B-form of mono 2-nitrobutyl phenylmalonate (0.7 G. 0.0025 mol.) was reacted as above to give the penicillin 0.8g. (64%) as a cream coloured noncrystalline solid.

EXAMPLE 11 Mono- 1 .3-dibromo-2-propyl phenylmalonate Phenylmalonic acid (27 g. 0.15 mol.) in dry ether (80 ml.) was converted to the mono acid chloride and reacted with l.3 dibromopropanol-2 (32.7 g. 15.5 ml. 0.15 mol.) by the method of Example 7(a) to give the crude ester 43.1g. (75.6%) m.p. 77C. Recrystallisation from benZene/6080C light petroleum gave 35.4 g. (62.1%) of a colourless crystalline solid m.p. 77-79C. (Found: C3804; H,3.51; Br,42.20. C H O B requires (5.37.93; H.318; Br. 42.06%).

a-( l.3-Dibromo-2-propoxycarbonyl )benzylpenicillin sodium salt Mono 1,3-dibromo-2-propyl phenylmalonate (7.6 g. 0.02 mol.) was converted to the acid chloride and reacted with o-aminopenicillanic acid (4.32 g. 0.02 mol.) according to the method of Example 7(b) to give the penicillin 8.5 g. (70.8%) as a colourless non crystalline solid.

EXAMPLE 12 Mono l-ethoxycarbonylethyl phenylmalonate a-(1-Ethoxycarbonylethoxycarbonyl)benzylpenicillin sodium salt Mono l-ethoxycarbonyl phenylmalonate (2.8g. 0.01 mol.) was converted to the acid chloride and reacted with 6-aminopenicillanic acid (2.16g. 0.01 mol.) according to the method of Example 7(b) to give the penicillin 4.3g. (86%) as a colourless non-crystalline solid.

EXAMPLE 13 Mono-a-ethoxycarbonylbenzyl phenylmalonate Phenylmalonic acid (27g. 015 mol.) in dry ether ml. was converted to the mono acid chloride and reacted with ethyl-DL-mandelate (27g. 0.15mo1) according to the method of Example 7(a) to give the crude ester 42.8g. (83.4%). After three recrystallisations from benzene/6080C light petroleum a colourless crystalline solid 13.2g. (25.7%) was obtained m.p. 97C. (Found: C,66.33; H.553. C d-1, 0 requires C6666; H.5.30%).

a-( a-Ethoxycarbonylbenzyloxycarbonyl )benzylpenicillin sodium salt Mono a-ethoxycarbonylbenzyl phenylmalonate (3.42g. 0.01 mol.) was converted to the acid chloride and reacted with o-aminopenicillanic acid (2.16g. 0.01 mol.) according to the method of Example 7(b) to give the penicillin 36 g. (64.1%) as a colourless non crystalline solid.

EXAMPLE 14 Mono 2.2,2-trichloroethyl 3-thienylmalonate In an analagous reaction to that described in Example 7(a) for phenylmalonic acid 3-thienylmalonic acid (9.3g. 0.05 mol.) in dry ether (30 ml.) was converted to the mono acid chloride and reacted with 2.2.2-

trichloroethanol (7.48g. 0.05 mol.) to give the crude ester as an oil. Trituration of the oil with 4060C boiling range light petroleum gave a colourless crystalline solid 328g. (20.7%) m.p. 4648C. (Found: C,34.37; H.237; 0.33.68. 5.9.93. C H O, Cl S requires C3404; H.222; (133.52, 5,1001%).

a-( 2,2,2-Trichloroethoxycarbonyl )-3-thienylmethylpenicillin sodium salt Mono 2,2,2-trichloroethyl 3-thieny1malonate (085g. 0.0027 mol.) was converted to the acid chloride and reacted with 6-aminopenicillanic acid (0.578g. 0.0027 mol.) by the method described in Example 7(b) to give the penicillin lg. (69.5%) as a cream coloured non-crystalline solid.

EXAM PLE 15 Mono-( 2-nitro-2-methy1-1-propyl)phenylmalonate Phenylmalonic acid (27 g., 0.15 mol) in dry ether (80 ml.) was converted to the mono-acid chloride and reacted with 2-nitro2-methylpropanol-l (17.85 g., 0.15 mol.) by the method described in Example 7(a). The crude product was recrystallised from benzene to give 38.5 g. (67.6%) of colourless crystals m.p. 9l-93C. 7

Found: C5590; H.549; N483. C H O N requires: C.55.50; H.538; N.4.98%.

a-( 2Nitro-2-methyl l -propyloxycarbonyl)benzylpenicillin sodium salt Mono-2-nitro-2-methyll -propylphenylmalonate (2.81 g 0.01 mol.) was converted to the acid chloride and reacted with 6-aminopenicillanic acid (2.16 g., 0.0] mol.) by the method of Example 7(b) to give the penicillin sodium salt 3.41 g. (68.1%) as a colourless noncrystalline solid.

EXAMPLE l6 Mono-2-ethylsulphonylethyl phenylmalonate Phenylmalonic acid (27 g., 0.15 mol.) in dry ether (80 ml.) was converted to the mono-acid chloride and reacted with 2-ethylsu1phonyl ethanol (20.7 g, 0.15 mol.) by the method described in Example 7(a). The crude product was recrystallised from ethylacetatel60 80 petroleum ether to give 16g. (35.6%) of colourless crystals m.p. 1l21 14C. Found: C 1 .85; H, 5.25; 5,1102. C H O -S requires: C. 52.00; H 5.37; S, 10.66%

a-( 2-Ethylsulphonylethoxycarbonyl )benzylpenicillin sodium salt Mono-Z-ethylsulphonylethyl phenylmalonate (3.0g, 0.0lmol.) was converted to the acid chloride and reacted with -aminopenicillanic acid (2.16 g. 0.01 mol.) by the method of Example 7(b) to give the penicillin sodium salt 3.4 g. (65.4%) as a colourless nonerystalline solid.

EXAMPLE 17 MOno-2.2,2-tribromoethylphenylmalonate Phenylmalonic acid (27g 0.15 mol.) in dry ether (80 ml.) was converted to the mono-acid chloride and reacted with 2 2.2-tribromoethanol (42.45 g. 0.15 mol.) by the method described in Example 7(a). The crude product was recrystallised from benzene/6080 petroleum ether to give 51.9 g. (78%) of colourless crystals m.p. l081 C. Found: C,29.87; H.216; Br. 54.16; C,,H,,O,,Br requires: C, 29.69; H.104; Br 53.88%

a-( 2,2,2-Tribromoethoxycarbonyl )benzylpenicillin sodium salt Mono-2.2.2-tribromoethyl phenylmalonate (4.45 g. 0.01 mol.) was converted to the acid chloride and re acted with 6-aminopenicillanic acid (2.16 g. 0.01 mol.) by the method of Example 7(b) to give the penicillin sodium salt 3.8g. (57.2%) as a colourless noncrystalline solid.

EXAMPLE l8 Mono-2,2,2-trifluoromethyl phenylmalonate Phenylmalonic acid (27 g., 0.15 mol.) in dry ether ml.) was converted to the mono-acid chloride and reacted with 2,2,2-trifluoroethanol 15g, 0.15 mol.) by the method described in Example 7(a). The crude product was recrystallised from benzene/6080 petroleum ether to give 21.5 g. (54.7%) of colourless crystals m.p. 6769C. Found: C,50.64; H380; F 22.20. C H O F requires: C. 50.38; H.346; F, 21.74%.

a-( 2,2.2-Trifluoroethoxycarbonyl )benzylpenicillin sodium salt Mono-2.2,2-trifluoroethyl phenylmalonate (2.62 g. 0.01 mol.) was converted to the acid chloride and reacted with 6-aminopenicillanic acid (2.16 g. b 0.0] mol.) by the method of Example 7(b) to give the penicillin sodium salt 3g. (62.2%) as a colourless noncrystalline solid.

EXAMPLE 19 Mono-[bis-(l,3-ethylsulphonyl)2-propy1]phenylma lonate Phenylmalonic acid (27g. 015 mol.) in dry ether (80 ml.) was converted to the mono-acid chloride and reacted with bis-1.3-ethyl sulphonyl-2-propanol (36.6 g., 0.15 mol.) by the method described in Example 7(a). The crude product crystallised from the reaction mixture and was filtered off. The solid was heated in water and the hot solution decanted from insoluble oil, cooled and allowed to crystallise to give the product 3.2g. (5.2%). m.p. ll1-l 13C.

a-[bis-( 1,3-ethylsulphonyl) 2-prop0xycarbonyl]benzyl sodium salt Mono-[ bis( 1,3-ethylsulphonyl )2-propyl ]phenylmalonate (1.6 g.. 0.00394 mol.) was converted to the acid chloride and reacted with 6- aminopenicillanic acid (0.851 g., 0.00394 mol.) by the method of Example 7(b) to give the penicillin sodium salt 0.7g. (28.4%) as a colourless non-crystalline solid.

EXAMPLE 20 Mono p-methoxyphenyl phenylmalonate 0.01 mol.) was converted to the acid chloride and reacted with 6-aminopenicillanic acid (2.16 g.. 0.01

mol.) by the method of Example 7(b) to give the penicillin sodium salt 4.2g. (83%) as a colourless noncrystalline solid.

EXAMPLE 2i Mono-p-chlorophenyl phenylmalonate Phenylmalonic acid (27g, 0. l5mol.) in dry ether (80 ml.) was converted to the mono-acid chloride and reacted with p-chlorophenol (19.28g. 0.l5 mol.) by the method of Example 7(a). The crude product was recrystallised from benzene 6080 petroleum ether to give 262g. (60.1%) of pale yellow crystals m.p. l23l25C. Found: C,65.3l; H,4.3l; Cl,l 1.29. C, H ,O Cl.l/2 C H requires: C.65.57; H.428; Cl, 10.75%.

a-(p-Chlorophenoxycarbonyl)benzylpenicillin sodium salt Mono-p-chlorophenyl phenylmalonate (2.9g, 0.0l mol.) was converted to the acid chloride and reacted with 6 aminopenicillanic acid (2.l6g., 0.0l mol.) as in Example 7(b) to give the penicillin sodium salt 2.6g. (5 l7n) as a colourless non-crystalline solid.

EXAMPLE 22 Mono-p-tolyphenylmalonate Phenylmalonic acid (27g, 0.l5 mol.) in dry ether (80 ml.) was converted to the mono-acid chloride and reacted with p-cresol 162g. 0.l5mol.) as described in Example 7(a). The crude product was recrystallised from benzene/60-80 petroleum ether to give 33g. (SL570) of colourless crystals. m.p. l22-l24C Found: C. 72.64; H542. C H O .l/2 C H requires: C.73.77; H,5.54%.

a-(p-Tolyloxycarbonyl)benzylpenicillin sodium salt Mono-p-tolylphenylmalonate (2.7g, 0.0l mol.) was converted to the acid chloride and reacted with 6- aminopenicillanic acid (2.l6g., 0.0l mol.) as in Example 7(b) to give the penicillin 3.6 g. (73.5%) as a co lourless non-crystalline solid.

EXAMPLE 23 oz-( o-Carboxyphenoxycarbonyl )benzylpenicillin di-sodium salt R.CR.KIJ*NH- ca--cii c (IJ---N Cli-(DOH.

EXAMPLE 24 Mono-phenyl-2-thienylrnalonate 2-Thienylmalonic acid (738g, 0.0396 mol.) suspended in dry ether (30 ml.) was treated with oxalylchloride (7.2 ml. The solution was refluxed with stirring for 2V2 hours, cooled and concentrated under re duced temperature and pressure. Benzene was added and evaporated to remove the last traces of oxalyl chloride. The residue was treated with a solution of phenol (4g, 0.0425 mol.) in dry ether (10 ml.) and stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with sodium bicarbonate solution. The aqueous alkaline extracts were aciditied with 5N hydrochloric acid and exhaustively extracted with methylene chloride. The combined or ganic extracts were washed with brine, dried and stirred with decolourising charcoal. After filtration, the solvent was evaporated to give a buff coloured solid. One recrystallisation from benzene gave mono-phenyl Z-thienylmalonate 306g. (30%) as a crystalline solid m.p. -94C (d). Found: C,59.52; H394; S,l l.88.C, H SO requires C.59.5l;H,3.84;S,12.22%

a-(Phenoxycarbonyl)2-thienylmethylpenicillin sodium salt Mono-phenyl Z-thienylmalonate (2.3 lg., 0.0088 mol.) in dry ether (15 ml.) was converted to the acid chloride with oxalylchloride (3.8 ml.) and reacted with o aminopenicillanic acid by the method of Example 7(b) to give the penicillin sodium salt 129g. (30%) as a light brown amorphous solid.

What is claimed is:

l. A composition for the treatment of infections in humans and animals due to Gram-positive and Gramnegative bacteria comprising an anti-bacterially effec' tive amount of a mono-ester of an wearboxypenicillin wherein the a-carboxy group is esterified and having the formula:

or a non-toxic pharmaceutically acceptable salt thereof, wherein R is phenyl or 3-thienyl and R is phenyl or lower alkyl phenyl in a pharmaceutically acceptable non-toxic carrier formulated for oral administration in unit dosage form.

2. A composition according to claim 1 wherein R is phenyl and R is phenyl.

3. A composition according to claim 1 wherein R is 3-thienyl and R is phenyl.

4. A composition according to claim 1 in which the composition is in unit dose capsule form, each capsule containing l25l,000 mg of a a-carboxypenicillin mono-ester.

5. A composition according to claim 1 in which the composition is in unit dose capsule form, each capsule containing 250-500 mg of a-carboxypenicillin monoester.

6. A composition according to claim 1 in which the composition is in unit dose tablet form, each tablet con taining l25l.000 mg of a-carboxypenicillin monoester.

mcmoo NH cii-cit l l-1l 'oo---u CH-COOH or a non-toxic pharmaceutically acceptable salt thereof, wherein R is phenyl or B-thienyl and R is phenyl or lower alkyl phenyl incorporated in a pharmaceutically acceptable non-toxic carrier in unit dosage form.

9. A method according to claim 8 wherein each unit dose contains -1 ,000 mg of a-carboxypenicillin mono-ester.

10. A method according to claim 8 wherein each unit dose contains 250-500 mg of a-carboxypenicillin mono-ester.

11. A method according to claim 8 wherein R is phenyl and R is phenyl.

12. A method according to claim 8 wherein R is 3- thienyl and R is phenyl. 

1. A COMPOSITION FOR THE TREATMENT OF INFECTIONS IN HUMANS AND ANIMALS DUE TO GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA COMPRISING AN ANTI-BACTERIALLY EFFECTIVE AMOUNT OF A MONOESTER OF AN A-CARBOXYPENICILLIN WHEREIN THE A-CARBOXY GROUP IS ESTERIFIED AND HAVING THE FORMULA:
 2. A composition according to claim 1 wherein R is phenyl and R1 is phenyl.
 3. A composition according to claim 1 wherein R is 3-thienyl and R1 is phenyl.
 4. A composition according to claim 1 in which the composition is in unit dose capsule form, each capsule containing 125-1,000 mg of a Alpha -carboxypenicillin mono-ester.
 5. A composition according to claim 1 in which the composition is in unit dose capsule form, each capsuLe containing 250-500 mg of Alpha -carboxypenicillin mono-ester.
 6. A composition according to claim 1 in which the composition is in unit dose tablet form, each tablet containing 125-1,000 mg of Alpha -carboxypenicillin mono-ester.
 7. A composition according to claim 1 in which the composition is in unit dose tablet form, each tablet containing 250-500 mg of Alpha -carboxypenicillin mono-ester.
 8. A method of treating infections in humans and animals due to Gram-positive and Gram-negative bacteria which comprises orally administering to said humans and animals an antibacterially effective amount of a mono-ester of an Alpha -carboxypenicillin wherein the Alpha -carboxy group is esterified and having the formula:
 9. A method according to claim 8 wherein each unit dose contains 125-1,000 mg of Alpha -carboxypenicillin mono-ester.
 10. A method according to claim 8 wherein each unit dose contains 250-500 mg of Alpha -carboxypenicillin mono-ester.
 11. A method according to claim 8 wherein R is phenyl and R1 is phenyl.
 12. A method according to claim 8 wherein R is 3-thienyl and R1 is phenyl. 